The present Proposal involves a series of clinical and laboratory studies designed to test whether Alpha-difluoromethylornithine (DFMO) can be used to enhance the treatment of human small cell lung carcinoma (SCC). DFMO is a suicide inhibitor of ornithine decarboxylase activity (ODC)--this enzyme catalyzes the formation of putrescine from ornithine which is the first and rate-limiting step in biosynthesis of the polyamines putrescine, spermidine and spermine. The present investigations are constructed upon background observations that: (a) human SCC in cell culture is unusually sensitive to DFMO; (b) in a nude mouse model, DFMO causes regression of established human SCC implants after 5-6 weeks of oral administration when initial tumor burden is low. Based on these observations and results in other laboratories, a Phase I study of DFMO in humans was recently carried out and completed at our Institution. The current Proposal will expand on our initial clinical and laboratory results to fully assess the clinical efficacy of DFMO in treating SCC. Two clinical studies will be carried out in patients with SCC and both will be based on: (a) the recently completed Phase I study of DFMO in humans; (b) the laboratory data outlined above. The first study will assess the therapeutic efficacy of DFMO as a consolidation agent given following initial cytoreductive therapy in patients with SCC--this approach is based on the nude mouse data suggesting the need for long-term treatment in the setting of low tumor burden for DFMO to be effective. The second study will test the efficacy of DFMO as a modifier agent when given simultaneously with combination chemotherapy. The laboratory studies will expand the nude mouse data to establish: (a) in-vivo heterogeneity for the response of SCC to DFMO--for this purpose, multiple culture lines of SCC, with different rates of response to DFMO in vitro, will be used for establishing nude mouse implants; (b) the toxicity and therapeutic efficacy of using DFMO simultaneously with combination chemotherapy in defined time sequences; and (c) levels of circulating DFMO and tumor tissue levels of DFMO, the 3 polyamines, and the polyamine synthesizing enzymes (ODC and SAM-DC) which correlate with therapeutic response. These studies will allow us to further define the timing and dosage of DFMO in the treatment of SCC. METHODS: clinical trials; radioassays; high pressure liquid chromatography; amino acid analysis.